DISSERTATION ON
RISK FACTORS FOR HEPATOTOXICITY FOLLOWING HAART IN HIV PATIENTS
M.D. DEGREE BRANCH I - GENERAL MEDICINE Of
THE TAMILNADU DR.M.G.R. MEDICALUNIVERSITY, CHENNAI, INDIA.
DEPARTMENT OF MEDICINE TIRUNELVELI MEDICAL COLLEGE
TIRUNELVELI, INDIA.
APRIL 2011
ii
CERTIFICATE
This is to certify that the dissertation entitled “RISK FACTORS FOR HEPATOTOXICITY FOLLOWING HAART IN HIV PATIENTS”submitted by Dr.A.T.MAASILA, appearing for Part II M.D.
Branch I General Medicine Degree Examination in April 2011, is a bonafide record of work done by him under my direct guidance and supervision in partial fulfilment of regulations of the Tamil Nadu Dr. M.G.R. Medical University, Chennai. I forward this to the Tamil Nadu Dr.M.G.R. Medical University, Chennai, Tamil Nadu, India.
Dr.Arumugapandian @ MohanM.D., Dr.J.Kaniraj Peter M.D .,
Associate Professor, Professor &Head of Department, Department of Medicine, Department of Medicine,
Tirunelveli Medical College, Tirunelveli Medical College,
&Hospital,Tirunelveli &Hospital,Tirunelveli.
Tamilnadu, India. Tamilnadu, India.
Dean
Tirunelveli Medical College & Hospital (TVMCH), Tirunelveli, India.
iii
DECLARATION
I solemnly declare that the dissertation titled " RISK FACTORS FOR HEPATOTOXICITY FOLLOWING HAART IN HIV PATIENTS” is done by me at Tirunelveli Medical College hospital, Tirunelveli under the guidance and supervision of Associate Professor, Dr.Arumugapandian @ MohanM.D.,
The dissertation is submitted to The Tamilnadu Dr. M.G.R.Medical
University towards the partial fulfilment of requirements for the award of M.D. Degree (Branch I) in General Medicine.
Place: Tirunelveli Dr.A.T.MAASILA
Date: Postgraduate Student
M.D. General Medicine Department of Medicine Tirunelveli Medical College Tirunelveli
iv
v
ACKNOWLEDGEMENT
I humbly submit this work to the Almighty who has given the health and ability to pass through all the difficulties in the compilation and proclamation of this blue print.
I wish to express my sincere thanks to our Dean, Dr.N.Palaniappan M.D.,and Medical Superindentent Dr. Jimla Balachandran M.D (OG),for permitting me to use the resources of the institution for my study/Thesis work.
It is with immense honour and gratitude that I specially thank Dr.J.Kaniraj Peter M.D, Professor and Head of the Department,
Tirunelveli Medical College & Hospital, for his constant support and encouragement throughout the course
Words fall short to describe my deep sense of gratitude and respect that I express my utmost thanks to my guide, Dr.Arumugapandian @ Mohan M.D., Associate Professor in Department of Medicine, Tirunelveli Medical College & Hospital, a teacher with excellent clinical skills and knowledge for his unfailing inspiration, affectionate guidance and advice throughout the course of the present study. His valuable suggestions, sympathetic, helping nature and encouragement enabled me to attain this achievement.
vi
My sincere thanks to my Assistant Professors of the department Dr.Kandasamy@Kumar M.D, D.M, and Dr.Marchwin Kingston Samuel for their words of encouragement and support they offered during difficult periods.
I thank Dr.Karthickeyan M.D., D.M., for his expert guidance, suggestions and constructive criticism which were invaluable for my study.I would like to thank my department colleagues and friends for their constant support and co-operation.
I thank Dr.Pethuru M.D, for his help in statistical analysis and technical assistance in making this dissertation presentable.
I thank the entire ART Team for the extreme cooperation extended to me without whom the study would not have been possible. I especially like to thank Dr.John jude joshua, Senior Medical Officer, ART centre for his guidance.
I would like to thank the Institutional Ethical Committee for approving my study.I am extremely thankful to my family members for their continuous support.
Last but not the least, I thank all the patients who cooperated with the study in spite of their illness and stigmata. This work would be complete and successful, if it had contributed, even in the smallest possible way to alleviate their suffering.
vii
LIST OF ABBREVIATIONS USED ACTG AIDS Clinical Trials Group
AIDS Acquired immunodeficiency syndrome ALT Alanine aminotransferase
APV Amprenavir
ARLI Antiretroviral drug-related liver injury ART Antiretroviral therapy
AST Aspartate aminotransferase ATV Atazanavir
AZT Zidovudine (also known as ZDV) BMI Body Mass Index
CCR5 Chemokine receptor 5 CD4 Cluster differentiation CMV Cytomegalovirus
CT Computed Tomography CTX Co-Trimoxazole
d4T Stavudine ddC Zalcitabine ddI Didanosine
DNA Deoxyribonucleic acid EBV Epstein-Barr virus EFV Efavirenz
viii
ERCP Endoscopic Retrograde Cholangio Pancreatography FDA Food & Drug Administration
FTC Emtricitabine GBV-C Hepatitis G Virus
HAART Highly Active Anti-Retroviral Therapy HAV Hepatitis A Virus
HBsAg Hepatitis B Surface Antigen HBV Hepatitis B Virus
HCV Hepatitis C Virus HDV Hepatitis D Virus HSV Herpes Simplex Virus HHV-8 Human Herpes Virus 8
HIV Human Immunodeficiency Virus IDV Indinavir
IFN Interferon INH isoniazid LPV lopinavir
MAC Mycobacterium Avium Complex MTB Mycobacterium Tuberculosis
NNRTI Non-Nucleoside Reverse Transcriptase Inhibitor NRTI Nucleoside Reverse Transcriptase Inhibitor NFV Nelfinavir
ix
NVP Nevirapine
OI Opportunistic Infections PI Protease Inhibitor
RNA Ribonucleic Acid RTV Ritonavir
SMX Sulfamethaoxzole SQV Saquinavir
3TC lamivudine T20 Enfuvirtide TMP Trimethoprim TDF Tenofovir TPV Tipranavir
ULN Upper Limit of Normal VZV Varicella zoster virus
x
LIST OF TABLES
SL.NO TABLES Page
No 1.1 Major causes of Liver injury in HIV - infected patients 3 2.1 Liver toxicity of commonly used anti- HIV medications 29
2.2 Common causes and risk factors 30
2.3 Clinical presentation of Hepatotoxicity 31
2.4 Mechanisms of Hepatotoxicity 31
2.5 Monitor for Liver Enzymes and Hepatotoxicity Symptoms 39
4.1 Patient Selection 41
4.2 Duration of HAART 46
4.3 ATT 46
5.1 Descriptive Statistics 50
5.2 Analysis of age with LFT 50
5.3 Analysis of sex with LFT 51
5.4 Analysis of BMI with LFT 51
5.5 Analysis of Alcohol with LFT 52
5.6 Analysis of CD4 counts with LFT 52
5.7 Analysis of co infection HBV with LFT 53
xi
5.8 Analysis of co infection HCV with LFT 53
5.9 Analysis with combination of HBV, HCV & Alcohol with
LFT 54
5.10 Analysis between various Treatment Regimens with LFT 54 5.11 Analysis of Duration of HAART and Hepatotoxicity 55 5.12 Analysis of Patients receiving HAART and ATT drugs with
Hepatotoxicity 56
xii
LIST OF FIGURES
Sl. No FIGURES Page
No
2.1 Interplay between bilirubin metabolism, Gilbert's genotype
and atazanavir (ATV) or indinavir (IDV) use. 20
2.2 Hepatic safety profile of antiretroviral drugs 29
2.3 Mechanisms of Hepatotoxicity 37
2.4 Algorithm for the management of patients with ART-related
Hepatotoxicity. 39
5.1 Sex Distribution 47
5.2 Alcohol 48
5.3 HAART Drugs 48
5.4 Incidence of HBV 49
5.5 Incidence of HCV 49
6.1 Analyses of combination of Alcohol, HBV&HCV with LFT 59
6.2 Analysis of HBV with LFT 60
6.3 Analysis of HCV with LFT 61
6.4 Analyses of combination of alcohol, HBV, HCV with LFT 61
xiii
TABLE OFCONTENTS
S.NO TITLE Page No
1 INTRODUCTION 1
2 REVIEW OF LITERATURE 15
3 AIM OF THE STUDY 40
4 MATERIALS & METHODS 41
5 RESULTS 47
6 DISCUSSION 57
7 CONCLUSION 63
8 SUMMARY 64
9 REFERENCES 65
Introduction
1
INTRODUCTION
Human immunodeficiency virus (HIV) infection/Acquired Immunodeficiency Syndrome is a global pandemic, with cases reported from virtually every country. With more than 35 million fatalities, the AIDS epidemic now ranks alongside the influenza pandemic of the early 1900s and the Bubonic plague of the fourteenth century in terms of fatalities.[1]
Statistics for the end of 2008 indicate that around 33 million people are living with HIV, the virus that causes AIDS. Each year around 2.7 million more people become infected with HIV and 2 million die of AIDS.[2]Although HIV and AIDS are found in all parts of the world, the worst affected region is sub-Saharan Africa, where in a few countries more than one in five adults are infected with HIV. The epidemic is spreading most rapidly in Eastern Europe and Central Asia, where the number of people living with HIV increased to 67% between 2001 and 2008.
Gastroenterological manifestations are quite common in advanced HIV infection/ AIDS and are sometimes the initial manifestations or AIDS defining illness. Liver involvement is unique since it can be because of direct involvement, opportunistic infections (OI) with co-infection of one or more hepatotoxic viruses, or because of toxicity due to antiretroviral drugs.[3]
2
HEPATOBILIARY MANIFESTAIONS OF HIV/AIDS:
Liver disease has assumed a far greater importance as a cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV) because of their increased life expectancy as a result of antiretroviral therapy (ART). Presence of liver disease is a frequent finding in AIDS. Hepatomegaly may be detected on examination in most patients.
Hepatomegaly is usually associated with one or more biochemical test abnormalities, although significant jaundice due to parenchymal disease is uncommon.
As with other organ systems, the spectrum of hepatic infections in patients with HIV evolves as immunocompromise advances. Hepatobiliary disease in HIV-infected patients can be divided into two groups: Those with severe immunosuppression, who commonly have opportunistic infections, and those with suppressed HIV viral loads and minimal immunosuppression.
Clinical manifestations of hepatobiliary disease can vary from no symptoms to liver failure.
3
Table 1.1 - MAJOR CAUSES OF LIVER INJURY IN HIV-INFECTED PATIENTS
DRUGS
ART: NRTI, NNRTI, PI Antimicrobial agents:
Antituberculosis (INH, rifampin)
Macrolides (clarithromycin, azithromycin)
Antifungal (ketoconazole, itraconazole, fluconazole) Antipneumocystis (TMP-SMX, pentamidine, dapsone) INFECTIONS
Viral (HAV, HBV, HCV, HDV, GBV-C, CMV, HSV, VZV, EBV)
Mycobacterial (Mycobacterium avium, Mycobacterium tuberculosis, other Mycobacteria)
Fungal (cryptococcus, histoplasma, coccidioides, candida)
Protozoan (pneumocystis, toxoplasma, microsporidia, cryptosporidium) BILIARY TRACT INFECTIONS
HIV cholangiopathy, Acalculous cholecystitis NEOPLASMS AND VASCULAR LESIONS Kaposi sarcoma, Lymphoma, Peliosis hepatitis STEATOSIS WITH LIPODYSTROPHY
HCV/HIV coinfection Drug-associated (PI and NRTI).
4 DRUGS:
Drug-induced liver injury has emerged as the most prevalent cause of liver test abnormalities and is related to the increasing array of antiretroviral medications. Use of prescription or non-prescription drugs as well as herbal remedies should also be considered a cause of abnormal liver test results in the HIV-infected patient. Before HAART, drug hepatotoxicity was most commonly due to sulfonamides, and the increased frequency of adverse reactions to these medications is well recognized in AIDS.
The lactic acidosis syndrome, characterized by marked hepatomegaly, steatosis, metabolic lactic acidosis, and liver failure, is now well recognized.
The liver tests typically show a hepatocellular pattern but can be normal or minimally increased. Hepatic steatosis is evident on imaging of the liver.
Although reversal has occurred in some patients following drug withdrawal, most patients have worsening disease and death. Liver transplantation is curative.
The incidence of drug induced hepatotoxicity, its mechanisms, evaluation, management, analyses of various studies on the risk factors and prognosis are described in detail in Literature review.
INFECTIONS:
Viral Infections, of the liver are often because of herpes viridae family. CMV is detected frequently in autopsies of severely immunosuppressed patients with CD4 counts less than 100/mm3 and is often
5
a component of systemic involvement .CMV infects every type of cell within the liver. CMV infection is being detected earlier now owing to pp65 antigen flow cytometry and CMV polymerase chain reaction.
Hepatitis secondary to HSV occurs in patients with extensive herpetic ulcers elsewhere. Pathologically, HSV hepatitis is characterized by multinucleated hepatocytes and Cowdry type A intranuclear inclusion bodies that may be differentiated from those of CMV by specific immuno- histochemistry. Varicella-zoster virus, EBV, and adenovirus are the other agents responsible for viral hepatitis in patients with HIV.
Clinical manifestations and histologic features of viral hepatitis from HBV, HCV, or hepatitis D virus are altered in the presence of HIV coinfection but in remarkably different ways for each virus. Because of common epidemiologic risks of transmission including sexual and parenteral exposures, coinfection of hepatitis B virus (HBV) with HIV is common. Decreased response to HIV-ART and a higher risk of hepatic decompensation was observed in HBV/HIV-coinfected patients compared with those of HIV monoinfected patients. [4] Clinical and autopsy studies in AIDS patients have reported up to a 90% sera prevalence of hepatitis B markers indicating past or present infection.
Concurrent HIV and HBV infections lead to alterations of HBV antigen-antibody display, viral replication, and clinical consequences.
Several reports have described reappearance of hepatitis B surface antigen
6
(Bag) in HIV-infected patients previously thought to be immune to hepatitis B virus as indicated by the presence of anti-HBs.[4]Recurrence of Bag may arise from either reinfection or reactivation with advanced immunodeficiency. In addition, there is an accelerated loss of naturally acquired anti-HBs even in those patients who remain HBsAg negative. With loss or reduction in immunity to HBV, there is an increased prevalence of hepatitis B e antigen expression, elevated mean levels of DNA polymerase, and increased titers of anti–hepatitis B core antigen.[5]
Acquisition of the chronic carrier state is also much more likely in the HIV-infected patient, especially if infection occurs when immunodeficiency is more advanced. Thus, a larger proportion of patients with HIV and hepatitis B infections have a chronic carrier state, with highly infectious serum and body fluids, compared with those who are HIV negative.
Although HIV infection leads to more prevalent chronic HBV carriage, it appears to attenuate the severity of biochemical and histologic liver disease in most, but not all patients.
In one study, the mean alanine aminotransferase (ALT) level correlated with CD4 lymphocyte count. The mechanism for reduced hepatitis B virus–related liver injury following HIV infection is not certain but has been attributed to a diminution in lymphocyte-mediated hepatocellular injury as a result of HIV effects on lymphocytes. In those patients without serologic evidence of past or present hepatitis B virus and
7
HIV infection, vaccination appears to be ineffective, regardless of the stage of immuno compromise. Sometimes the institution of HAART in a chronic carrier of hepatitis B virus can have catastrophic consequences.
Patients may develop an acute flare of hepatitis that can be severe leading to fulminant hepatic failure. However, the proportion of coinfected patients who develop an acute hepatitis B flare following use of HAART is unknown. It is believed that reconstitution of immune function with HAART leads to production of antibody that is directed to infected hepatocytes as in the normal host. Inclusion of lamivudine, which has potent antiviral effects on hepatitis B virus, in the HAART regimen may reduce the likelihood of acute hepatitis B.[5]The consequences of HIV infection on delta hepatitis appear similar to those of HBV, although far fewer patients have been studied.
The prevalence of HCV in those with HIV infection depends on the risk group evaluated and the assay used. Prevalence is highest in injection drug users (52% to 89%)[6] and hemophiliac patients with HIV, whereas in military populations and non–drug users, the prevalence is much lower, ranging from 1% to 11%. Assaying antibodies to hepatitis C virus alone, rather than hepatitis C virus RNA, may underestimate the true prevalence, because loss of antibody may occur with progression of immunodeficiency.[4],[5]Unlike hepatitis B virus, the clinical course of hepatitis C virus appears to worsen as HIV-related immune compromise
8
advances. This has been best documented in HIV infected hemophiliac patients. Studies in large cohorts of hemophiliac patients have demonstrated dramatic increases in hepatitis C virus RNA levels with progressive HIV disease, associated with aspartate aminotransferase (AST) elevations and hepatomegaly. Coinfected patients also have a higher rate of active cirrhosis on biopsy and an accelerated course to clinical cirrhosis and liver failure.
Factors that predict fibrosis and progression to cirrhosis in coinfected patients include: older age at infection, higher alanine aminotransferase levels, higher inflammatory activity, alcohol consumption of more than 50 g/day and CD4+ T cell count of less than 500 cells/mm.[3],[7],[8]
The mechanism for this more rapid disease course is unknown but has been similarly recognized in other immunocompromised patients. Because patients with late-stage HIV often have multiple life- threatening infections, HCV alone is not an independent determinant of mortality.
However, as HIV-infected patients are living longer owing to HAART, hepatitis C virus–induced liver disease and its consequences (e.g., hepatocellular cancer) are assuming more clinical relevance. Like hepatitis B, hepatitis C virus does not cause progression of HIV disease.[6]The effect of HAART on hepatitis C viral dynamics and liver injury is variable. Some studies have found attenuation of disease, whereas others had documented exacerbations reflected by increases in serum transaminases. Hepatitis C viral load has also been variably affected.[9]The role of interferon therapy for
9
HIV/HCV coinfected patients remains unsettled. α-Interferon is less effective for treating hepatitis C virus liver disease in coinfected patients.
More recently, combination therapy of Peg-interferon and ribavirin has shown promise.[10]
Mycobacterial Infections, most common opportunistic pathogen affecting the liver. Infection with MAC manifests with systemic symptoms and signs, such as fever, abdominal pain, wasting, and biliary obstruction secondary to enlarged lymph nodes at the porta hepatis. It is ordinarily seen in late stage AIDS patients with CD4 count less than 50 cells/mm3. MAC is detected in 20% to 55% of autopsies and in 10% to 30% of liver biopsies in patients with AIDS. Blood cultures are the most sensitive test for diagnosis of MAC. On the other hand, liver biopsy showing diffuse, poorly formed noncaseating granulomas is necessary for definitive diagnosis of liver involvement. Liver tissue culture is needed to distinguish between different Mycobacterium species. Liver biopsy has been reported to be more sensitive than bone marrow biopsy in diagnosing disseminated mycobacterial infection in AIDS.[11]Extrapulmonary Mycobacterium tuberculosis (MTB) infection involving the liver occurs in 5% to 10% of HIV-related tuberculosis cases and may present with tuberculous liver abscess in severely immune compromised patients.[12]As the virulence of MTB is greater than in the other species of Mycobacterium, it may infect the patients who have higher CD4 counts, more than 200/mm3.[13]The specific
10
diagnosis is made by culture and polymerase chain reaction of blood, urine or tissue specimen including liver. Acid-fast bacilli may be seen in the liver histology, which is typically characterized by presence of caseating granulomas. Rarely, liver infections with other mycobacterial species such as Mycobacterium kansasii, Mycobacterium xenopi, and Mycobacterium genavense have also been reported.
Fungal Infections infecting the liver are Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis and Candida albicans. They are uncommon and ordinarily seen in the setting of disseminated disease, in patients with less than 100 CD4 cells/mm3. Liver histology often reveals poorly formed granulomas with minimal inflammatory reaction.
Meningitis is the most common manifestation of cryptococcal disease in HIV-infected patients. Liver involvement occurs because of haematogenous spread. The common presenting features are fever and hepatosplenomegaly. Progressive disseminated histoplasmosisis often the first sign of immunodeficiency in patients with AIDS in endemic areas.[14]
Constitutional symptoms along with hepatosplenomegaly and lymphadenopathy are the common features.
C. immitis infection presents with pulmonary involvement, hepatic infection is again secondary to disseminated disease. Systemic infection and liver involvement with candidiasis are quite rare unless the patients are neutropenic. The symptoms are nonspecific such as nausea, vomiting,
11
abdominal pain, and hepatomegaly. C. neoformans and H. capsulatum may be rapidly detected by polysaccharide capsular antigenemia; There are also rare reports of Aspergillus fumigatus causing liver abscess and disseminated Sporothrix schenckii involving the liver. .
Protozoa, are rare pathogens causing infections in patients with AIDS.
The routine prophylaxis with trimethoprim/sulfamethoxazole (TMP-SMX) has reduced the incidence of Pneumocystis jirovecii, Toxoplasma gondii, and Listeria monocytogenes. In the past P. jirovecii (formerly Pneumocystis carinii) hepatitis was associated with the prophylactic use of aerosolized pentamidine for pneumocystis pneumonia.[15],[16] Inhalation failed to provide adequate drug levels to extra pulmonary sites and up to 39% of such patients developed extrapulmonary spread.[17] Abdominal CT scan may demonstrate diffuse and punctate calcifications in the liver. Liver biopsy shows foamy nodules that are periportal or diffuse containing numerous Pneumocystis cysts that stain with Gomori's methenamine-silver.
T.gondii also involves the liver rarely through haematogenous dissemination and may present with granulomatous disease or hepatitis.
Diagnosis is made by culture or microscopic examination of Giemsa-stained specimens. Microsporidial infection of the liver is rare. Light microscopy reveals focal granulomatous and suppurative necrosis, mainly in the portal area, accompanied by characteristic spores.
Strongyloides stercoralis, a helminth of the nematode family, may result in a hyperinfection syndrome in the immuno compromised patient. The liver is
12
involved through the haematogenous spread of the larvae from the gastrointestinal tract. Entamoeba histolytica may invade the bowel wall and spread to the liver, forming an abscess. Reactivated Leishmania donovani is another rare infection of the liver .The biliary tree including the gall bladder, is a common site of infection in HIV infected patients with immunosuppression. It may be involved in the form of acalculous cholecystitis or cholangiopathy.
Hepatic microabscesses or macroabscesses are most likely to occur if the patient is neutropenic, especially following chemotherapy for non- Hodgkin's lymphoma. Kaposi's sarcoma, which is caused by infection with human herpesvirus 8 (HHV-8) has a predilection for periportal regions of the liver and is seen in 10% to 15% of liver biopsies. Tumor nodules appear grossly as violaceous or hemorrhagic masses within hepatic parenchyma.
Microscopically, the characteristic spindle cells and vascular slits of Kaposi's sarcoma usually directly abut normal-appearing liver tissue. Hepatic involvement by non-Hodgkin's lymphoma may be the index manifestation of AIDS in homosexual men and may be the primary site of the neoplasm. The lesions are usually focal and may be large. In addition, Hodgkin's disease in the AIDS patient tends to be more aggressive histologically and clinically, spreading rapidly to extranodal sites making liver involvement more likely.
Bacillary peliosis hepatitis may be caused by either Bartonella henselae or Bartonella quintana.
13
Biliary tract involvement in AIDS may result in marked liver test abnormalities and right upper quadrant symptoms, jaundice is unusual. A syndrome resembling sclerosing cholangitis with papillary stenosis is well recognized and has been termed AIDS cholangiopathy. Patients characteristically develop significant upper abdominal pain in association with marked elevation of alkaline phosphatase, and minimal elevations of bilirubin, AST, and ALT.
Other less common causes of biliary tract disease in AIDS include primary bile duct lymphoma, epithelial angiomatosis, lymphomatous nodal obstruction, Kaposi's sarcoma, and biloma. In addition, chronic pancreatitis or choledocholithiasis may lead to biliary obstruction, although their incidence is not clearly increased in HIV infection.[3][4]
EVALUATION:
The initial decision in evaluating the AIDS patient with jaundice, hepatomegaly, or both, is to determine whether the findings are due to intrahepatic or extrahepatic disease. Simultaneous disease in both sites must also be considered. A history of mild jaundice, often in association with fever and constitutional symptoms, is more consistent with intrahepatic disease, whereas symptoms of deep jaundice associated with pain of relatively acute onset suggest extrahepatic disease.
Careful review of medications, both prescription and non- prescription, is essential. Because the clinical history and the finding of symptomatic hepatomegaly are nonspecific, further evaluation is always
14
necessary. Elevations of ALT or AST or both are common, but neither the pattern nor the extent of elevation of these tests appears to correlate with specific findings in the liver. Significant elevation of the transaminases favours a drug-induced or viral cause. In contrast, marked elevation of alkaline phosphatase correlates statistically with the presence of MAC infection in the liver in AIDS when extrahepatic obstruction is absent.
The indications for liver biopsy for the patient in whom intrahepatic disease is suspected are not well defined. Biopsy is appropriate when symptomatic, treatable disease of the liver is suspected and when a specific diagnosis of hepatic disease is needed. An extrahepatic cause for jaundice is suggested on CT or ultrasonography by the presence of dilated ducts or other biliary and/or pancreatic abnormalities. Once extrahepatic obstruction is recognized, the possibility of papillary stenosis associated with AIDS cholangiopathy must be considered as well as the possibility of choledocholithiasis or other disorders, depending on the imaging studies.
Further evaluation, when indicated, may include endoscopic retrograde cholangiopancreatography (ERCP) if CT or ultrasonography demonstrates extrahepatic biliary ductal dilatation. Ampullary and duodenal biopsy specimens or bile and/or biliary cytology (with appropriate staining) collected during ERCP can be examined for the presence of viruses, protozoa, or neoplastic cells. [2],[3],[4]
Review of literature
15
REVIEW OF LITERATURE
The advent of highly active antiretroviral therapy (HAART) has dramatically reduced the clinical impact of infection with HIV1,2.The terminology “highly active antiretroviral therapy”(HAART) refers to use of combinations of three antiretroviral agents for treatment of HIV infection.
To date, most clinical experience with use of HAART in treatment-naïve individuals has been based on three types of combination regimens: NNRTI based (1 NNRTI + 2 NRTI), PI-based (1-2 PI + 2 NRTI), and triple NRTI- based regimens. Most experience in India is with NNRTI based regimens.
HAART INDUCED LIVER DISEASE:
Highly active antiretroviral therapy (HAART) has dramatically changed the course of HIV infection, having decreased the morbidity and mortality derived from classical opportunistic infections. In the recent era of ART therapy (between 2000 and 2005), the estimated expected survival for a 25-year-old HIV-infected person was 39 years, compared with only 7 years for the same individual in the pre-ART era.[18]
Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity, mortality and treatment discontinuation in HIV-infected patients.[19] Prevention and management of ARLI have emerged as major issues among HIV-infected patients in the era of HAART.[20]Virtually every licensed antiretroviral medication has been associated with liver enzyme elevations, although certain drugs may cause liver injury more frequently
16
than others. Discerning the role of HAART in hepatotoxic reactions of HIV patients may be difficult due to frequent preexisting liver pathology, such as that arising from infection with hepatitis B or C virus. Moreover, poly pharmacy is common in HIV-infected individuals, and a very large number of medications are known to have effects on liver function and drug metabolism.
In addition, certain comorbidities, such as chronic hepatitis B (HBV) or hepatitis C (HCV) infection, may predispose patients to ARLI.[21] Several major mechanisms of ARLI have been described, including metabolic host- mediated injury, hypersensitivity reactions, mitochondrial toxicity, and immune reconstitution phenomenon. The management of ARLI should be based on its clinical severity and underlying pathogenic mechanism.
Therefore, it is imperative to rule out other potential aetiologies before discontinuing HAART drugs.
CLINICAL IMPACT:
With the widespread use of HAART and the availability of new antiretroviral medications, ARLI has gained prominent attention owing to its negative impact on clinical outcomes. Drug-associated hepatotoxicity also creates an economic burden on already strained medical budgets, since additional visits and hospital admissions are often required for appropriate patient care and management.[19] Furthermore, antiretroviral drug discontinuation hampers maintenance of HIV suppression.
17
The severity of ARLI may range from the absence of symptoms to liver decompensation, and the outcome can range from spontaneous resolution to liver failure and death.[22],[23] In one study, severe hepatotoxicity with acute hepatic necrosis was recognized in 2% of HIV-infected patients dying from liver disease. Furthermore, in a large ACTG cohort of nearly 3000 patients initiating HAART, the most common grade 4 adverse events were liver related; this risk was increased in patients with underlying chronic viral hepatitis.[24]
Fortunately, the vast majority of episodes of ARLI are asymptomatic, and most ALT elevations resolve spontaneously, as described for many other medications, probably through a process called 'adaptation'.[25] However, in a minority drug-induced liver injury can be overt and have serious consequences. Therefore, it is critically important for the clinician to understand risk factors associated with poor outcomes and the pathogenic mechanisms of disease.
In a recent American study, which evaluated the causes of death of HIV-infected individuals, discontinuation of ART due to hepatotoxicity increased from 6% in 1996 to 31.8% in 1998-1999 among those mortalities . More recently, Kramer and colleagues have highlighted the increase in the number of cases of fulminant liver failure in HIV/HCV-coinfected individuals during the HAART era, even after excluding patients with advanced liver disease and adjusting by alcohol intake.
18
Drug liver toxicity has impacted on the recommendations for antiretroviral therapy in certain scenarios. Thus, the use of nevirapine (NVP) has been recommended to be avoided as part of post-exposure prophylaxis regimens.
The reason for that was the occurrence of fulminant hepatitis in two cases and severe liver toxicity in 12 other healthy subjects who received a NVP- including HAART regimen after HIV exposure.
However, NVP seems to be safe when administered to mother and child as a single dose for prevention of mother-to-child HIV transmission.[3],[4]
DEFINITION OF LIVER INJURY:
ARLI is defined by elevations in liver enzymes in serum, with alanine aminotransferase (ALT) characteristically greater than aspartate aminotransferase (AST). To date, there has been broad variability in the criteria used in clinical studies to categorize the severity of hepatotoxicity.
Some studies have utilized ALT parameters as minimal as two times the upper limits of normal.[26]while others have employed an absolute threshold (e.g., >100 IU/ml), regardless of baseline liver function tests.[27]
The clinical relevance of these elevations is uncertain.
More recently, the AIDS Clinical Trials Group (ACTG) has defined a grading scheme against the patient's baseline serum aminotransferase concentrations. For example, in patients with a normal prêtherapy ALT or AST, hepatic injury is graded as moderate or severe based on a 5-fold or 10-
19
fold increase in aminotransferases, respectively.[28]In patients with abnormal liver enzymes prior to therapy, a >3.5-fold or a 5-fold increase in ALT or AST is considered indicative of moderate or severe hepatotoxicity, respectively.[29]
DEFINITIONS OF HAART-ASSOCIATED HEPATOTOXICITY:
The AIDS Clinical Trials Group currently uses the following toxicity grading scale:
PATIENTS WITH NORMAL PRETREATMENT ALT/AST:
Grade 0 hepatotoxicity <1.25 times the ULN (upper limit of normal)
Grade 1 hepatotoxicity 1.25 to 2.5 times the ULN Grade 2 hepatotoxicity 2.5 to 5 times the ULN Grade 3 hepatotoxicity 5.1 to 10 times the ULN Grade 4 hepatotoxicity >10 times the ULN
There is a grading scale for the HAART-associated cholestasis:
Grade 0 cholestasis <1.1 times the ULN Grade 1 cholestasis 1.1 to 1.5 times the ULN Grade 2 cholestasis 1.6 to 2.9 times the ULN Grade 3 cholestasis 3 to 5 times the ULN Grade 4 cholestasis >5 times the ULN
For patients with elevated pre-treatment ALT/AST, changes are compared to baseline rather than upper limit of normal. Grades 0 and 1 are identical, but grade 2 is associated with ALT/AST 2.6 to 3.5 times baseline,
grade 3 is 3.6 to 5 t baseline.[30] Severe hep transaminase levels.
Liver function te the one hand, some dr increase γ-glutamyl tra often misinterpreted as this enzyme actually bilirubinaemia alone sh hyper bilirubinaemia m atazanavir.[31],[32],[33]
T Gilbert's syndrome, a ge
Figure 2.1-Interplay be atazan
20
to 5 times baseline, and grade 4 greater re hepatotoxocity is defined as grade 3 o
tion test abnormalities require careful inte me drugs (e.g., nevirapine and less freque
yl transpeptidase serum levels. This labor ted as a marker of liver damage, when isolat
ally reflects enzyme induction. Sim one should not be equated with liver injury
mia may be related to medications, such a This risk is increased in patients wi e, a genetic disorder .
y between bilirubin metabolism, Gilbert's azanavir (ATV) or indinavir (IDV) use.
reater than 5 times e 3 or 4 change in
interpretation. On frequently efavirenz) laboratory result is isolated elevation of . Similarly, hyper injury, since indirect such as indinavir or nts with underlying
rt's genotype and
21
On the other hand, drug-induced liver injury that is associated with an elevated direct bilirubin and clinical jaundice portends a poor clinical outcome. A cholestatic profile should only be considered when there is an associated increase in serum alkaline phosphatase as well as bilirubin.
Elevated aminotransferases also need to be interpreted within their clinical context. For example, increased liver enzymes in a patient with chronic HBV infection do not necessarily imply drug injury but may reflect HBV-related hepatic flares, which often occur during the natural course of the disease.
INCIDENCE AND RISK FACTORS:
After initiating HAART, the reported incidence of severe liver toxicity ranges from 2 to 18 %.[21],[27],[29],[34-42]
Differences in study outcomes may reflect heterogeneity in patient populations, frequency of liver enzymes determinations, other exogenous exposures (e.g., alcohol), medication prescribing patterns, prevalence of chronic viral hepatitis, and criteria used for defining severe hepatotoxicity.
Hepatitis B and C co-infections:
Liver toxicity, especially severe toxicity (grades 3 and 4),is clearly more frequent in HCV and/or HBV co-infected individuals treated with HAART.[33],[22-25],[34-38]
In one study, a higher risk of hepatotoxicity was found in patients carrying HCV genotype 3 (HCV-3) compared to other genotypes.[40] The clinical implications of this finding are 2-fold. On one hand, the presence of HCV-3 may impact on the selection of HAART
22
regimen, choosing those with less potential for hepatotoxicity. On the other hand, since genotype 3 shows a higher response to α-interferon (IFN)and ribavirin (RBV), anti-HCV treatment should be given if no major contraindication is present.
In addition to drug injury, flares in serum transaminase concentrations in a patient with chronic HBV can be related to several different factors, including viral rebound after withdrawal of effective anti-HBV therapy, break through of drug-resistant HBV strains or spontaneous flares of HBV viraemia.[41],[43-45]
The clinician must bear this in mind before misinterpreting hepatic flares as drug injury.
Alcohol:
Alcohol is a known heaptotoxin and its use has been associated with an increased risk of ARLI in the studies that have examined this variable.[21]Chronic use may also predispose to hepatocyte injury by increasing oxidative damage to mitochondrial DNA and depleting stores of glutathione, an important scavenger of free oxygen radicals.[46]
Other Predisposing Factors:
Multiple studies have demonstrated that the risk of liver injury is increased in those with aminotransferase elevations prior to initiating HAART.[35],[37-40]
Other risk factors associated with ARLI include older age
[7],female gender[40],[47],first exposure to antiretroviral treatment[41] and significant CD4 cell gains following HAART initiation.[29,48] More recently,
23
an association between the presence of advanced stages of liver fibrosis and greater risk of ARLI has been reported.[49]The mechanism for this observation is unclear, but it could be the consequence of compromised hepatic clearance with subsequent drug overexposure in patients with cirrhosis.[84]
ANTIRETROVIRALS:
Studies that have evaluated the risk of liver injury associated with a particular antiretroviral agent or class are often conflicting. The effect of a specific drug is difficult to ascertain because of the widespread use of combination therapy.
Nucleoside Reverse Transcriptase Inhibitors:
NRTIs are associated with low incidence of elevated liver enzyme values, 5% to 6%[29],[51],[52]
ranging from 7% with zidovudine, 9-13% with stavudine and 16% with didanosine.[53]Newer NRTI such as emtricitabine, abacavir and tenofovir are associated with a low incidence of mild asymptomatic aminotransferase elevations.[54]
Mitochondrial toxicity is an infrequent but distinctive type of hepatotoxicity associated with the use of NRTI that may evolve to acute liver failure with severe hepatomegaly and lactic acidosis.[55]This complication generally occurs after several weeks or months of NRTI treatment. However, nucleoside analogues differ widely in their propensity to induce mitochondrial toxicity. Potency estimations in vitro gave a
24
descending hierarchy of their potency: zalcitabine, didanosine, stavudine, zidovudine and, finally, abacavir, as least toxic.[54]In-vitro data support additive or synergistic mitochondrial toxicity of some NRTI combinations
[56]such as stavudine and didanosine.[56-58]
Two clinical entities of hyperlactatemia are associated with mitochondrial toxicity. The time to presentation of NRTI-related hyperlactatemia is reported to be 3 to 20 months, with a median time of 9 months. Many patients have a 2- to 4-week prodrome, the most common symptoms are nausea, vomiting, vague abdominal pain, and abdominal distension, the prognosis is usually good as long, as the use of NRTIs is stopped, but long-term sequelae may occur. The second associated mitochondrial injury is the lactic acidosis syndrome, reported to occur 1 to 4 Cases/1000 patient-years. This condition is much more ominous and is associated with multiorgan failure and a mortality rate of 30% to 100%
even if ART is stopped.[59]
Hypersensitivity reactions have been linked to abacavir and are characteristically seen in patients with HLA-B*5701 background.[60]Re exposure to abacavir can be fatal.Incidents of unexplained liver disease in HIV-infected individuals have recently been reported in which clinical manifestations of portal hypertension are often predominant. Didanosine exposure seems to be involved in almost all and nodular regenerative hyperplasia is a frequent histological finding.[61,62]
25
Nonnucleoside Reverse Transcriptase Inhibitors:
The incidence of elevated liver enzyme values with either drug has been reported to range from less than 2% to 20%.[63],[64] However, severe liver toxicity, occurring with early latency, has been reported in HIV- infected and HIV-seronegative individuals. Warnings against the use of nevirapine for post exposure prophylaxis were issued after some individuals developed hepatic failure requiring liver transplantation.[65]Concomitant use of NNRTIs and PIs also seems to increase the risk of elevated liver enzyme values.[66],[67],[68]
Women who have CD4 counts higher than 250 cells/mL are especially at risk for nevirapine- related fulminant hepatic failure.[69]Several studies continue to find women at greater risk than men for elevated liver enzyme values, especially with nevirapine, this finding remains unexplained.[70],[71]
Nevirapine seems to be associated with two types of toxicities. An initial hypersensitivity reaction characterized by rash, fever, and elevated liver enzyme values occurring in the first 4 to 6 weeks is thought to represent an idiosyncratic reaction of the host and is not related to the dose of the drug. For reasons that are unclear, women who have CD4 counts of 250 Cells/ml and higher and men who have CD4 counts of 400 cells/ml or
higher Seem to be at increased risk of this type of toxicity.[72]
Furthermore, a low body mass index is another independent risk factor for nevirapine hypersensitivity reaction.[70]
26
In addition, nevirapine has been associated with a late risk of toxicity occurring at 6 to 12 months.[73-75]This type of toxicity seems to increase in incidence over time, probably results from a direct effect of the drug, and is thought not to represent an immune- mediated process. Persons with an HLA-DRB1*0101 background have an increased propensity for developing nevirapine-associated hypersensitivity.[76-78]
Idiosyncratic Drug-related Toxicity:
In other studies, a different pattern of drug injury with nevirapine use has emerged, with onset of liver enzyme elevations occurring beyond 16 weeks of therapy, consistent with direct or idiosyncratic host-mediated liver injury.[47],[48]This late onset of hepatotoxicity with NNRTI is more common in patients with underlying chronic viral HBV and/or HBV&HCV infection, as has been described with many other antiretroviral agents. In patient populations that vary in terms of chronic viral hepatitis prevalence, NNRTI-associated liver injury can vary from 15%[48] to as low as 3%.[79]Specific genetic polymorphisms of metabolizing enzymes and drug transporters may also increase the risk of this complication.[80,81] It should be highlighted that hepatotoxicity with either nevirapine or efavirenz does not appear to increase the risk of developing liver injury on exposure to the alternative NNRTI.[82],[83]
27 Protease Inhibitors:
The phenomenon of ARLI became more evident after the introduction of PI drugs. Rates of hepatotoxicity from registration trials of various PI have ranged from 1% to 9.5%, but few patients had serious liver-related outcomes.[85]In comparison with other drugs in its class, full- dose ritonavir has consistently been shown to be more hepatotoxic.[29],[37],[41]
However, the use of low-dose ritonavir for pharmacokinetic boosting of other PI drugs appears to be safe.[86]
Although there are a few case reports of liver-related toxicity with indinavir, these were in association with advanced liver disease; dose reduction is recommended in patients with cirrhosis. Several cases of clinical hepatitis and hepatic decompensation, including some fatalities, have been associated with the use of tipranavir, particularly in patients with chronic HCV infection.[87],[88] Nelfinavir, saquinavir, atazanavir, fosamprenavir, lopinavir and darunavir are associated with a relatively safer liver toxicity profile.[89-96] Amprenavir has occasionally been associated with drug-related hypersensitivity reactions but only sporadically with severe hepatotoxicity.[97]
In patients taking PIs, the incidence of elevated liver enzyme values is higher in those who have HIV/HCV coinfection than in those who have HIV alone. Recently, an FDA black-box warning was issued for the use of ritonavir to boost tipranavir because of increased hepatotoxicity in
28
coinfected patients. Multivariate analysis also has shown that an increase in CD4 counts to more than 50 cells/mL from baseline, which may indicate an underlying immune- mediated process, is associated with increased risk of elevated liver enzyme values.[98]
New Antiretroviral Drug Families
The clinical development of aplaviroc, a CCR5 antagonist, was halted in 2005 after the occurrence of severe hepatotoxicity.[99]In contrast, maraviroc and vicriviroc appear to have safer hepatotoxicity profiles.
Enfuvirtide, the only approved fusion inhibitor, has demonstrated a consistent safety record in terms of liver toxicity.[100]Data on integrase inhibitors are still scarce, but to date MK-0518 has not been associated with any significant liver toxicity.[101]
29
Table 2.1 - Liver toxicity of commonly used anti- HIV medications
Drug type Drug name Pattern of injury Comments Protease inhibitor Indinavir
Saquinavir Nelfinavir Ritonavir
Hepatocellular, distinct histologic pattern including hepatocyte ballooning, Kupffer cell
activation, pericellular zone 3 fibrosis
< 10% of patients have transaminases
> 5 ULN Ritonavir inhibits P 450
NRTI ddC d4T
ddl AZT
Microvesicular steatosis
Mitochondrial toxicity manifesting as lactic acidosis NNRTI Nevirapine
Efavirenz
Hepatocellular NVP associated with grade 4
toxicity; FDA alert
CAUTION
SAFE
NRTI NNRT PI ENTRY
INHIBITORS
Figure 2.2 - Hepatic safety profile of antiretroviral drugs
RTVV
ddl D4T
AZT
ABV TDF
3TC FTC
NVP
EFV
TPV
APV DRV
ATV LPV
SQV NFV T20
30
Table 2.2 - Common causes and risk factors
MECHANISMS OF LIVER TOXICITY:
Drug-induced liver injury can be considered predictable (high incidence) or unpredictable (low incidence).[102]Liver injury may result from direct toxicity of the drug or its metabolites or may be an idiosyncratic response in persons with a characteristic genetic predisposition. The latency period between the initiation of therapy and the onset of liver disease provides clues to its aetiology.
Predictable hepatotoxic reactions are dose dependent and host independent, with the classic example being paracetamol (acetaminophen) toxicity. Early-onset toxicity (within a few days) is strong evidence for direct drug toxicity, particularly if there has been no previous exposure.
Unpredictable hepatotoxic reactions are host dependent and not dose related.[103]Unfortunately, the vast majority of drug reactions are
COMMON CAUSES AND RISK FACTORS Drugs
Obesity
Coinfection with hepatitis viruses Advanced disease
Older age Female gender
First exposure to antiretroviral treatment
Significant CD4 cell gains following HAART initiation.
31
unpredictable. They occur when the drug is transformed into an intermediate metabolite that is either toxic (host-mediated metabolism) or provokes an immunological response (hypersensitivity reaction).
Table 2.3 - Clinical presentation of Hepatotoxicity
EARLY ONSET LATE PRESENTATION
Interval 1-8 weeks 2-12 months
Mechanism Immune Mediated Host-mediated
idiosyncratic Role of Hepatitis C
Virus No Yes
Role of CD4 counts Yes No
Drugs( E.g) Nevirapine, Abacavir
Stavudine, Didanosine Ritonavir
Table 2.4- Mechanisms of Hepatotoxicity
MECHANISMS OF HEPATOTOXICITY Direct toxicity
Hypersensitivity reaction Mitochondrial toxicity Metabolic abnormalities
Immune reconstitution syndrome in HBV/HCV co-infection
Metabolic Host-mediated Injury:
Host differences in drug metabolism may lead to an excess of potentially harmful reactive drug metabolites when genetic polymorphisms affect critical metabolizing enzymes.[104]The latency of onset is long (from 2
32
to 12 months), which poses problems for patient monitoring.[105].Prototypical examples include isoniazid and troglitazone, these aberrant metabolic pathways may also underlie one form of drug injury seen in association with the nonnucleoside reverse transcriptase inhibitors (NNRTI) and the protease inhibitors (PI).[106],[107]
Some drugs may potentiate the activation of T cell death receptors and/or intracellular stress pathways, leading to increased oxidative stress.[108]In response, hepatocytes promote mechanisms of cytoprotection, such as the formation of heat shock proteins, which protect the liver against toxic metabolites.[104] This cytoprotective response may explain the spontaneous normalization of liver enzymes that may occur despite maintenance of HAART (or other medications, such as isoniazid).
Alternatively, the rise and fall of serum aminotransferase concentrations after initiation of medications may be related to a phenomenon of 'adaptation', whereby liver function tests normalize despite ongoing drug exposure.[109]
Hypersensitivity Reactions:
Allergic phenomena are idiosyncratic to the host, have an intermediate onset of latency (from a few days to 8 weeks) and are not dose related.
The incidence of hypersensitivity reactions is about 1 in 1000 in the general population but is more common in patients with HIV.[110] Prototypical examples include phenytoin and sulphonamides, which can cause rash,
33
fever, eosinophilia and hepatitis. The temporal relationship between symptoms and signs and the initiation of the suspected culprit drug are helpful in distinguishing this type of drug reaction. Clearly, rechallenges should be avoided if drug hypersensitivity is suspected.
Hypersensitivity reactions have been reported with nevirapine, abacavir and less frequently with amprenavir, both in HIV-infected patients and in subjects receiving HIV prophylaxis after potential exposure.[111]
These immune-mediated drug reactions may involve the generation of neoantigens formed by the covalent bonding of liver proteins with reactive drug metabolites.[104],[112]
Mitochondrial Toxicity:
Mitochondria play a major role in energy production and glucose and fat metabolism, but they are also the main source of reactive oxygen species, which can lead to cellular demise. The most infamous example of severe mitochondrial damage occurred with the use of the nucleoside analogue fialuridine for the treatment of HBV. During the initial stages of the study, several participants developed lactic acidosis and hepatic failure.[113] Chronic therapy with nucleoside reverse transcriptase inhibitors (NRTI) for the treatment of HIV can also lead to mitochondrial toxicity after long-term exposure. This drug class selectively inhibits DNA polymerase-γ, which is responsible for replication of mitochondrial DNA. Diminished mitochondrial function may lead to a decrease in oxidative phosphorylation,
34
which in turn leads to aberrations in pyruvate metabolism and accumulation of lactate.[114]
The presence of chronic HCV infection, which is quite prevalent in HIV- infected patients may increase a patient's susceptibility to antiretroviral drug- related mitochondrial stress and damage.[115]HCV core protein causes mitochondrial injury, leading to excessive production of reactive oxygen species.[116-118] This leads to oxidative stress, which is enhanced in the presence of tumour necrosis factor, alcohol or nucleoside analogues.
Consequently, exposure to any nucleoside analogues either for the treatment of HIV (e.g., didanosine) or for HCV [e.g., tribavirin (ribavirin)] may further enhance mitochondrial toxicity.[119]
Immune Reconstitution Phenomena:
ARLI associated with HAART-induced CD4 T cell recovery has been attributed to immune reconstitution phenomena, particularly in the setting of chronic HBV and occasionally in patients with chronic HCV.
Hepatitis B. Cell-mediated immunity plays a central role in the pathogenesis of chronic HBV.[120] For example, in an HIV/HBV coinfected patient with advanced immunosuppression, HBV replication generally increases but HBV-related liver inflammation lessens and transaminase levels decline.[121] Conversely, when HAART is initiated improved cellular immunity can lead to flares in liver enzymes [122] and spontaneous seroconversion [123] even in the absence of any anti-HBV active
35
drug.[124]Liver enzyme flares in HIV/HBV-coinfected patients taking antiretroviral therapy need to be carefully interpreted with concomitant evaluation of serum HBV DNA in order to assign causality correctly. Liver enzyme elevations in HIV/HBV-coinfected patients following initiation of antiretroviral therapy can be caused by (i) direct drug-related liver injury (ii) immune reconstitution in patients positive for HBV surface antigen (HBsAg), (iii) seroconversion in patients positive for HBV 'e' antigen and/or HBsAg, (iv) HBV reactivation in inactive carriers and occasionally in those with resolved HBV infection.
Hepatitis C. However, antibody responses to HCV do not necessarily correlate with reconstitution of cellular immune function and initiation of HAART does not imply restoration of HCV-specific T cell responses.[125]
Moreover, the role that cellular immunity plays in the pathogenesis of chronic HCV is not as clear as for HBV.[120]Finally, conflicting results have been reported on whether gains in absolute numbers of CD4 T cells correlate with flares of transaminases.[135],[136],[126],[127]
Although immune reconstitution remains an attractive theory and it may certainly explain clinical events in a subset of HIV patients with HCV [128],[129]
more evidence needs to be gathered before any conclusions can be drawn.
36
Novel Potential Mechanisms for Antiretroviral Drug-related Injury:
Hepatic Steatosis:
Insulin resistance, hyperlipidaemia and visceral adiposity are the metabolic and morphological abnormalities that have been intrinsically linked to the development of hepatic steatosis in the general population. [130]
These same metabolic and morphological aberrations coexist in a high percentage of HIV-infected patients and are known as the lipodystrophy syndrome.[131] Several studies have found that hepatic steatosis is highly prevalent in HIV-seropositive patients, particularly in those with chronic HCV and/or receiving NRTI drugs with high mitochondrial toxicity profiles.[132],[133]
Hepatic steatosis produces substrates for lipid peroxidation; this results in the basal formation of potentially harmful reactive oxygen species, which can lead to liver injury.[134],[136]
Furthermore, HCV genotype 3 infection, which induces hepatic steatosis through a virally mediated cytopathic effect has been associated with an increased risk of ARLI.[137-
139]These studies suggest that liver steatosis itself may be a predisposing factor for drug-related toxicity
Figure THERAPEUTIC MAN When Should Antiretro
Clinical decision balancing act. Stopping prevent serious conse potentially important the therapy, however, can le important principles nee Symptomatic hepati
elevations of transam after onset of sympt lead to serious liver i
37
ure 2.3 -Mechanisms of Hepatotoxicity MANAGEMENT:
etroviral Drugs Be Discontinued?
cision making regarding drug discontinuat pping medications at the very first sign of m
consequences. However, this approach tant therapy for a large number of patients. C , can lead to untoward outcomes. For patient les need to be emphasized.
hepatitis is of much greater concern than transaminases. The longer a patient continues symptomatic hepatitis, the more likely the
liver injury.
tinuation is often a n of mild injury can ach can sacrifice ents. Continuing with atient safety, several
than asymptomatic ntinues to take a drug ly the outcome will
38
ARLI associated with overt jaundice with increased direct bilirubin levels has a high mortality rate. Medications should be immediately discontinued.
If a patient complains of symptoms consistent with mitochondrial toxicity in association with an elevated lactate level, medications should be immediately discontinued.
If the patient has symptoms consistent with drug hypersensitivity, the medication should be stopped immediately and readministration can be fatal.
Medications should be discontinued promptly if plasma ALT or AST is greater than 10 times the upper limit of normal (grade 4), even if the patient is asymptomatic.[140],141]For patients with advanced liver disease, more conservative management should be exercised to avoid hepatic decompensation
Spontaneous Improvement in Transaminases Despite Drug Continuation:
In assessing drug toxicity, mild elevations of serum transaminases
are commonly seen and often improve despite administration of the same drug.[142] This has also been observed with the antiretroviral
medications, particularly with PI use. Based upon these data, some authors have suggested that PI-containing HAART does not need immediate adjustment but simply careful monitoring.[143] It should be emphasized that most of these patients had asymptomatic elevations of transaminases.
39
Always consider alternative causes for hepatitis including viral hepatitis, cholecystitis, opportunistic infections and alcohol or cocaine use.
Table 2.5- Monitor for Liver Enzymes and Hepatotoxicity Symptoms Time After Initiation
of HAART
Monitor for Liver Enzymes and Hepatotoxicity Symptoms
0–1 month Every 2 weeks
18 weeks Monthly
Week 19 onward Every 3 months
Figure 2.4 - Algorithm for the management of patients with ART-related Hepatotoxicity.
Aim of the study
40
AIM OF THE STUDY The study was conducted with the objective of
1. Estimation of incidence of drug induced hepatotoxicity in patient receiving HAART therapy for HIV/AIDS
2. To analyse the risk factors that are associated with drug induced hepatotoxicity in these patients.
Materials & methods
41
MATERIALS & METHODS
About 1250 patients who receive ART were screened and patients with evidence of liver dysfunction were isolated. Study population was selected as follows.50 adult patients of both sexes infected with HIV and fulfil the WHO criteria for clinical AIDS receiving HAART for a period of more than 1 month were included in the study.
Table 4.1 – Patient Selection
PATIENT SELECTION INCLUSIVE CRITERIA
Patients with HIV infection
i. who receive HAART therapy for > 1 month
EXCLUSION CRITERIA
i. Patients with base line LFT abnormal
ii. Evidence of extrahepatic cause of jaundice iii. Past history of jaundice
iv. Clinical evidence of liver disease at the institution of HAART v. Antenatal mothers
vi. Children < 13 years
